A multistep synthesis of 4-6-(hexylcarbamoyloxy)hexylcarbamoyloxy!-piperidine-1 -carboxylic acid 4-phenoxyphenyl ester (1) as disclosed in the cited European Patent Application is shown in Scheme I where intermediate hydroxy compounds are reacted with phosgene or a phosgene equivalent and the resultant mixed carbonic acid diesters are used to aryloxycarbonylate or alkoxycarbonylate an appropriate amine. Thus, 4-phenoxyphenol (2) is treated with 4-nitrophenyl chloroformate (NPC) and condensation of the corresponding carbonate (3) with 4-hydroxypiperidine affords 4-hydroxy-1-piperidine-carboxylic acid 4 -phenoxyphenyl ester (4). Repeating the NPC activation step with the latter intermediate and the following condensation of carbonate (5) with 6-aminohexanol yield 4-(6 -hydroxyhexyl)carbamoyloxy!-piperidine-1-carboxylic acid 4phenoxyphenyl ester (6). To complete the synthesis of (1), the alcoholic function of this intermediate is activated again with NPC and treated with hexylamine, or reacted directly with hexylisocyanate. ##STR1##
Although useful for laboratory preparations, the above described synthesis of the title compound is less suitable for a commercial scale process. Obvious disadvantages include high cost of reagents (NPC and hexylisocyanate), a necessary recrystallization of intermediates, and a modest overall yield. Moreover, small amounts of by-products, such as symmetrical carbonates, carbamate-carbonates and ureas form in each step, and these impurities accumulate to make crystallization of the final product difficult. Additionally, the (4-phenoxy) -phenoxycarbonyl group is not completely inert under the described reaction conditions. The prior art patent application suggests the benzyloxycarbonyl moiety as an alternative, removable N-protecting group, however, the syntheses of the title compound from 1-benzyloxycarbonyl-4-hydroxypiperidine or analogous N-carbonylated species does not give a significantly better profile of impurities in the crude final product than when the phenoxyphenyl carbamate ester of 4-piperidinol is formed in the first step of the reaction sequence (Scheme I).